We are comparing the prophylactic therapeutic effects of lithium and carbamazepine in a double-blind, randomized, crossover design, followed by a period of treatment with both drugs in combination in outpatients with manic-depressive illness. Each drug phase lasts up to one year. We intend to explore the possible differential clinical efficacy of lithium, carbamazepine, and the combination, and assess possible clinical and biological correlates of response. We have added a fourth (one year) phase to the study consisting of sodium valproate in combination with lithium. We now have entered 53 patients (50 of whom have entered the randomized drug trial) and plan to recruit a total of 60 patients. Patients will have the following tests: hematological and thyroid indices, 24-hour urine collection for urinary free cortisol and neurotransmitter metabolites, TRH stimulation, DST, lumbar puncture, EEG, MRI, EKG, and an extensive battery of neuropsychological tests including assessment of psychosensory symptoms. Patients will also have a detailed life chart of their course of illness. A number of self- and observer-ratings are performed. Thirty-six patients have completed the first drug phase and 26 patients have also completed the second drug phase. In the first phase with lithium, 11 of 17 patients were able to complete the year and 6 of 11 patients failed; one patient had to stop because of severe acne. With carbamazepine, 8 of 19 patients were able to complete the year and 11 of 19 patients failed; 5 patients had to stop because they developed a rash. A total of 37 patients have been administered carbamazepine (this includes patients who have not completed a full one-year phase) and 8 (22%) have had to stop because of a drug rash. of the 53 patients who have entered the study, 12 have dropped out. Eight patients have entered the fourth arm of the study, consisting of valproate in combination with lithium; several of these are responding extremely well.